The present invention concerns the use of blocker compounds of calcium channels and/or channels activated by 3xe2x80x25xe2x80x2 cyclic guanosine monophosphate (cGMP), in the field of treating retinal pathologies, and more particularly retinal diseases resulting from photoreceptor degeneration, in humans or animals, such as retinitis pigmentosa or other pathologies substantially involving the photoreceptors, especially age-related macular degeneration.
Retinitis pigmentosa designates a group of these degenerative diseases of the photoreceptors (Berson, 1996) leading to blindness.
Numerous mutations affecting various rod proteins, and potentially the cause of this disease, have been described. Among these mutations can be mentioned those affecting the genes of proteins implicated in the phototransduction cascade, such as rhodopsin, transducin, phosphodiesterase, arrestin, or structural proteins such as peripherin.
The rd (retinal degeneration) mouse has been studied for more than 70 years as a model of retinitis pigmentosa (Farber et al., 1994), inasmuch as the process of retinal degeneration is similar to that observed in the pigmentary retina, the death of the retinal rods being followed by an unexplained loss of the retinal cones. Moreover, the causal mutation was localized in the gene encoding the xcex2 sub-unit of cGMP-phosphodiesterase (PDE) (Bowes et al., 1990), as in certain families affected by the disease (McLaughlin et al., 1993).
PDE is activated during the phototransduction cascade by the xcex1 chain of transducin, itself activated by light-stimulated rhodopsin. Activated PDE hydrolyzes cGMP, thus reducing the concentration of cGMP and hence the number of open cGMP-dependent channels, the final consequence being a decrease in the conductance of cations such as Na+ and Ca2+ and in turn a reduction of the depolarization current of the photoreceptors into obscurity. In the rd mouse, Farber and Lolley (1974) have shown that an abnormal increase of the cGMP concentration precedes the degeneration of the photoreceptors. The toxicity of cGMP at high concentrations was next established for normal photoreceptors (Lolley and Farber, 1977; Ulshafer et al., 1980).
Several therapeutic approaches intended to prevent photoreceptor loss are at present undergoing investigation in rd mice. It was therefore described that in vivo gene therapy permits retarding a death of photoreceptors for six weeks after sub-retinal injection of a replication-deficient recombinant adenovirus which contains the cDNA encoding murine PDE (Bennett et al., 1996). Photoreceptor transplantation (Gouras et al., 1994, Silverman et al., 1989) was described as permitting preservation of the cone photoreceptors (Mohand-Said et al., 1997). The interpretation of this effect in terms of the paracrine mechanism agrees with the increase of the photoreceptor survival observed in coculture with healthy photoreceptors (Mohand-Said et al., 1998) or after in vivo or in vitro application of trophic factors such as fibroblast or neuronal growth factors (LaVail et al., 1998).
Nevertheless, no treatment for retinal diseases resulting from photoreceptor degeneration is available at present, apart from prescription of vitamin A for retinitis pigmentosa (Berson, 1996).
The present invention particularly concerns providing pharmaceutical compositions that can be used in the field of treating retinal diseases resulting from photoreceptor degeneration in humans or animals.